Insulin-like Growth Factor (IGF)-II Binding Specificity Of IGF Binding Protein-6: Structural And Functional Studies.
Funder
National Health and Medical Research Council
Funding Amount
$265,630.00
Summary
Insulin-like growth factor II (IGF-II) is a protein which is involved in normal growth. However, in some circumstances it may also stimulate cancer growth. IGF binding protein-6 (IGFBP-6) binds to IGF-II and stops its activity. One of the major challenges of modern biology is understanding why some proteins bind to other proteins. Proteins fold in various ways and have specific three-dimensional structures. Two proteins which bind strongly to each other have structures which fit each other like ....Insulin-like growth factor II (IGF-II) is a protein which is involved in normal growth. However, in some circumstances it may also stimulate cancer growth. IGF binding protein-6 (IGFBP-6) binds to IGF-II and stops its activity. One of the major challenges of modern biology is understanding why some proteins bind to other proteins. Proteins fold in various ways and have specific three-dimensional structures. Two proteins which bind strongly to each other have structures which fit each other like a 'lock and key'. The aim of this project is to understand how IGFBP-6 binds to IGF-II by looking at its three-dimensional structure. Using this information, it may be possible to develop new treatments which can inhibit IGF-II activity and therefore may be useful in the treatment of some cancers.Read moreRead less
Pathways Involved In The Insulin-like Growth Factor (IGF)-independent Actions Of IGF Binding Protein-6
Funder
National Health and Medical Research Council
Funding Amount
$550,725.00
Summary
Insulin-like growth factors (IGFs) are important proteins that regulate growth. When not regulated properly, diseases such as cancer can occur. A family of IGF binding proteins regulates IGFs. IGFBPs may inhibit IGFs and we have shown that one of them, IGFBP-6, decreases growth of some experimental cancers. As well as regulating IGFs, some IGFBPs alter cell behaviour independently of IGFs, and we found that IGFBP-6 stimulates cell movement in this way. We will now determine how this happens.
Endocrine And Autocrine Regulation Of Breast Cancer Cell Growth By IGF Binding Protein-3 (IGFBP-3).
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
The insulin-like growth factor (IGF) system of growth factors and their regulatory proteins is essential for normal growth, but is also involved in a number of overgrowth disorders. Some clinical studies have shown that a high level of IGF-I in the blood increases the risk of breast cancer in some women, but if the protein which carries it in the circulation, IGFBP-3, is also high, the risk is reduced. It has therefore been suggested that IGFBP-3 may be useful in the treatment of breast cancer. ....The insulin-like growth factor (IGF) system of growth factors and their regulatory proteins is essential for normal growth, but is also involved in a number of overgrowth disorders. Some clinical studies have shown that a high level of IGF-I in the blood increases the risk of breast cancer in some women, but if the protein which carries it in the circulation, IGFBP-3, is also high, the risk is reduced. It has therefore been suggested that IGFBP-3 may be useful in the treatment of breast cancer. This is supported by laboratory studies showing that IGFBP-3 can inhibit cell division and stimulate cell death in many cell types, including breast cells. However, some cells are resistant to IGFBP-3 s inhibitory effects, and in some cases IGFBP-3 may stimulate cells to grow and divide. In fact, the amount of IGFBP-3 present in breast tumours is highest in the fastest growing, most malignant tumours, suggesting that IGFBP-3 may be stimulating their growth. Our laboratory data indicates that breast cancer cells which produce a high level of IGFBP-3 grow faster as tumours than cells which produce little or no IGFBP-3. We believe that this is because IGFBP-3 interacts with another hormone system which is involved in rapid tissue growth, the EGF system, and increases its ability to stimulate breast cells to divide. These observations raise a number of important questions: how does IGFBP-3 interact with the EGF system to stimulate tumour growth; does IGFBP-3 from the blood promote the growth of EGF-sensitive tumours; and can the interaction between IGFBP-3 and the EGF system be abolished, or switched from growth stimulatory to growth inhibitory, thus inhibiting tumour growth. Answering these questions will provide important new information regarding IGFBP-3 s stimulatory and inhibitory actions, and the role of endocrine IGFBP-3 in tumour growth, and have the potential to lead to the development of novel therapies involving IGFBP-3 for the treatment of overgrowth disorders.Read moreRead less
Determinants Of Insulin-like Growth Factor (IGF) Binding And Biological Actions Of IGF Binding Protein-6
Funder
National Health and Medical Research Council
Funding Amount
$399,750.00
Summary
Proteins are complex structures usually consisting of a number of distinct regions. Each of these regions may serve different roles. Insulin-like growth factors (IGFs) are important proteins involved in regulating the growth and other properties of cells. The actions of IGFs are in turn regulated by a family of binding proteins (IGFBPs). The aim of this project is to determine the range of actions of one of these IGFBPs and which parts of this IGFBP are involved in these actions. This may lead t ....Proteins are complex structures usually consisting of a number of distinct regions. Each of these regions may serve different roles. Insulin-like growth factors (IGFs) are important proteins involved in regulating the growth and other properties of cells. The actions of IGFs are in turn regulated by a family of binding proteins (IGFBPs). The aim of this project is to determine the range of actions of one of these IGFBPs and which parts of this IGFBP are involved in these actions. This may lead to new treatments for diseases in which cell growth is disturbed e.g. cancer and diabetes.Read moreRead less
Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Sensitivity And Signalling In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$414,343.00
Summary
The growth of all tissues in the body depends on many growth factors, hormones and other proteins which work together to control cell division. Some of these factors stimulate the division of the cells which make up the body tissues, and some inhibit it, so that a balance of these stimulators and inhibitors ensures that tissues do not grow too fast, or too large. The development of breast cancer and the growth of breast tumours is thought to be due to uncontrolled or faulty actions of the protei ....The growth of all tissues in the body depends on many growth factors, hormones and other proteins which work together to control cell division. Some of these factors stimulate the division of the cells which make up the body tissues, and some inhibit it, so that a balance of these stimulators and inhibitors ensures that tissues do not grow too fast, or too large. The development of breast cancer and the growth of breast tumours is thought to be due to uncontrolled or faulty actions of the proteins and hormones which regulate the way breast cells multiply. One protein which normally regulates the division of breast cells is IGFBP-3. We have found that in some breast cancer cells, IGFBP-3 is no longer able to inhibit cell division, and this may lead to tumour growth and invasion of other tissues. We are interested in finding out how IGFBP-3 normally controls breast cell proliferation, and why some breast cancers are resistant to IGFBP-3. To do this, we will use normal breast cells in culture to examine how IGFBP-3 interacts with other cellular factors to prevent cell division. We will then look at whether the breast cancer cells have changed so that they are no longer able to recognise IGFBP-3 as an inhibitory protein. This may be because of changes in the way IGFBP-3 binds to the breast cancer cell, or because of changes in the way it interacts with other proteins in the cell. Because IGFBP-3 is made by normal and breast cancer cells, we will also study whether the IGFBP-3 being made by breast cancer cells is normal, or if it changed in some way that makes it inactive. By understanding why some breast cancers are not inhibited by IGFBP-3, we will be able to design new and better methods of preventing, detecting and treating the growth of all breast tumours.Read moreRead less
Structural And Functional Investigation Into The Cooperation Of IGF And Vitronectin-binding Receptors In Cell Migration
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Breast cancer is the most commonly diagnosed form of cancer in Australian women, accounting for 26% of diagnosed cancers and 21% of cancer deaths among women. One in fourteen Australian and one in nine women worldwide will develop breast cancer in their lifetime. Significantly, approximately one in four of those diagnosed will die from their disease. The primary factor that determines survival is early diagnosis and treatment. Indeed, the primary tumour itself rarely causes death. Rather, the di ....Breast cancer is the most commonly diagnosed form of cancer in Australian women, accounting for 26% of diagnosed cancers and 21% of cancer deaths among women. One in fourteen Australian and one in nine women worldwide will develop breast cancer in their lifetime. Significantly, approximately one in four of those diagnosed will die from their disease. The primary factor that determines survival is early diagnosis and treatment. Indeed, the primary tumour itself rarely causes death. Rather, the dissemination of tumour cells to remote sites and the establishment of secondary tumours in critical sites in the body is the major mechanism of mortality. An understanding of the processes that lead to the establishment of secondary tumour bodies and strategies to halt the spread of cancer beyond the primary site are therefore highly valuable. Two factors thought to be pivotal in breast cancer metastasis are altered interactions with the microenvironment surrounding cells and exposure to increased levels of hormones and growth factors, such as the insulin-like growth factors (IGFs). We have recently found that IGFs form complexes with a protein called vitronectin, found in the microenvironment, and these complexes can stimulate increased migration of breast cancer cells. This project will examine the interaction of IGF and VN in stimulating cell migration and in particular, aims to identify the genes involved in the enhanced cell migration. In addition we will examine how the IGF:vitronectin complexes form and how these in turn interact with receptors on the surface of the cell. The data obtained will provide critical fundamental information that is necessary to develop targeted therapies for the treatment and control of breast cancer.Read moreRead less
Molecular Characterisation Of The Ligand-binding Domain Of The Mineralocorticoid Receptor
Funder
National Health and Medical Research Council
Funding Amount
$215,183.00
Summary
The steroid hormone aldosterone regulates blood pressure by controlling sodium retention. The important role of this hormone in blood pressure control is underlined by the fact that all known monogenetic hypertensive conditions involve aldosterone or sodium reabsorption. Aldosterone works by activating an intracellular 'receptor' protein that in turn switches on specific genes. The products of these genes act to produce sodium retention. Antagonists (blockers) of this receptor are used in the tr ....The steroid hormone aldosterone regulates blood pressure by controlling sodium retention. The important role of this hormone in blood pressure control is underlined by the fact that all known monogenetic hypertensive conditions involve aldosterone or sodium reabsorption. Aldosterone works by activating an intracellular 'receptor' protein that in turn switches on specific genes. The products of these genes act to produce sodium retention. Antagonists (blockers) of this receptor are used in the treatment of hypertension but have undesirable side effects. The design of new, more specific, antagonists has been slow because we do not understand how these drugs bind to the receptor and what effect they have on the protein. How the aldosterone receptor functions is poorly understood. This project aims to investigate the receptor in detail. We are in the process of determining regions of the receptor structure important for hormone binding. This information is vital for the design of new antagonists. The aldosterone receptor is unusual in that it is also activated by cortisol, a steroid hormone involved in stress and inflammation. By examining hormone binding it may be possible to determine if the two steroids activate the receptor in the same way. An understanding of how both natural hormones and synthetic antagonists function is impossible without thorough study of the receptor itself. We intend to examine fundamental aspects of aldosterone receptor function. In particular we wish to identify proteins that interact with the receptor. These proteins either enhance or inhibit the ability of the receptor to switch on genes and are vital to explaining the actions of both natural hormones and synthetic antagonists. Results from these experiments should advance our understanding of the basic biology of aldosterone action and its role in cardiovascular biology, and lead to the design of better receptor antagonists for use in the treatment of hypertension and cardiac fibrosis.Read moreRead less
Regulation And Effect Of The Growth Hormone, IGF-I, And IGF-Binding Protein Response To Acute Exercise
Funder
National Health and Medical Research Council
Funding Amount
$367,197.00
Summary
The body's ability to respond to physiological stress is vital to survival. This series of studies aims to examine the hormonal responses to physical exercise. In studies recently completed to determine how to detect Growth Hormone (GH) abuse in the Olympics, we have discovered a new system of hormones that respond to exercise. These Insulin-like Growth Factors (IGF) and their IGF-Binding Proteins (IGF-BP) are normally controlled by GH. The IGF-IGF-BP system normally acts to control of many cell ....The body's ability to respond to physiological stress is vital to survival. This series of studies aims to examine the hormonal responses to physical exercise. In studies recently completed to determine how to detect Growth Hormone (GH) abuse in the Olympics, we have discovered a new system of hormones that respond to exercise. These Insulin-like Growth Factors (IGF) and their IGF-Binding Proteins (IGF-BP) are normally controlled by GH. The IGF-IGF-BP system normally acts to control of many cellular and organ functions in many different tissues of the body. For example they stimulate protein accumulation and muscle growth, and have actions to control blood glucose in conditions like diabetes. Little is known about what regulates the production of the IGF and IGF-BPs in response to physical exercise. We aim to examine whether GH, either as an acute pulse as occurs naturally, or a direct effect of exercise that is not GH-mediated, is responsible for the increase in IGF and IGFBPs. This may uncover a new means of controlling this powerful hormonal system. In addition, we will examine whether GH or IGF-I, alone and together, influence the body's ability to respond to the stress of exercise (e.g., controlling fuel use, cardiovascular and kidney responses). Such information will allow greater understanding of this important hormonal system, so that in novel therapies may be developed for conditions such as normal ageing, the wasting states that accompany severe surgical or infectious stress, or conditions with abnormal blood glucose regulation such as diabetes. In addition, this information will permit greater sophistication in the detection of GH and related compounds in elite athletes. Unfortunately, GH is also being abused by non-elite athletes and high-school children. We believe our efforts will asist in the detection and prevention of these more general societal health issues.Read moreRead less